Anti-Integrin Therapy for Multiple Sclerosis

Integrins are the foremost family of cell adhesion molecules that regulate immune cell trafficking in health and diseases. Integrin alpha4 mediates organ-specific migration of immune cells to the inflamed brain, thereby playing the critical role in the pathogenesis of multiple sclerosis. Anti-alpha4 integrin therapy aiming to block infiltration of autoreactive lymphocytes to the inflamed brain has been validated in several clinical trials for the treatment of multiple sclerosis. This paper provides readers with an overview of the molecular and structural bases of integrin activation as well as rationale for using anti-alpha4 integrin therapy for multiple sclerosis and then chronicles the rise and fall of this treatment strategy using natalizumab, a humanized anti-alpha4 integrin

Nonmuscle myosin heavy chain IIA mediates integrin LFA-1 de-adhesion during T lymphocyte migration

Precise spatial and temporal regulation of cell adhesion and de-adhesion is critical for dynamic lymphocyte migration. Although a great deal of information has been learned about integrin lymphocyte function–associated antigen (LFA)-1 adhesion, the mechanism that regulates efficient LFA-1 de-adhesion from intercellular adhesion molecule (ICAM)-1 during T lymphocyte migration is unknown. Here, we show that nonmuscle myosin heavy chain IIA (MyH9) is recruited to LFA-1 at the uropod of migrating T lymphocytes, and inhibition of the association of MyH9 with LFA-1 results in extreme uropod elongation, defective tail detachment, and decreased lymphocyte migration on ICAM-1, without affecting LFA-1 activation by chemokine CXCL-12. This defect was reversed by a small molecule antagonist that inhibits both LFA-1 affinity and avidity regulation, but not by an antagonist that inhibits only affinity regulation. Total internal reflection fluorescence microscopy of the contact zone between migrating T lymphocytes and ICAM-1 substrate revealed that inactive LFA-1 is selectively localized to the posterior of polarized T lymphocytes, whereas active LFA-1 is localized to their anterior. Thus, during T lymphocyte migration, uropodal adhesion depends on LFA-1 avidity, where MyH9 serves as a key mechanical link between LFA-1 and the cytoskeleton that is critical for LFA-1 de-adhesion

Identification of the target self-antigens in reperfusion injury

Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heavy chain type II A and C as the self-targets in two different tissues. These results identify a novel pathway in which the innate response to a highly conserved self-antigen expressed as a result of hypoxic stress results in tissue destruction

Functional Flexibility of Exosomes and MicroRNAs of Intestinal Epithelial Cells in Affecting Inflammation.

Intestinal epithelial cells (IECs) are a mucosal immune barrier essential to coordinate host-microbe crosstalk. Sepsis is a systemic inflammatory syndrome with dysfunction in multiple organs including the intestine whose epithelial barrier is deregulated. Thus, IECs are a main contributor to intestinal permeability and inflammation in sepsis. Exosomes emerge as a mediator of intercellular and inter-organic communications. Recently, IEC-derived exosomes and their cargoes, such as microRNAs (miRNAs), in sepsis were shown to regulate the expression of proinflammatory mediators in the inflamed gut tissues. It is a compelling hypothesis that these IEC exosomes exhibit their dynamic activity to deliver their functional miRNA cargoes to immune cells in local and distant organs to regulate proinflammatory responses and alleviate tissue injury. Also, epithelial tight junction (TJ) proteins are downregulated on gut inflammation. Some of the IEC miRNAs were reported to deteriorate the epithelial integrity by diminishing TJ expressions in intestines during sepsis and aging. Thus, it is worth revisiting and discussing the diverse functions of IEC exosomes and miRNAs in reshaping inflammations. This review includes both iterative and hypothetical statements based on current knowledge in this field

Evaluating the lexico-grammatical differences in the writing of native and non-native speakers of English in peer-reviewed medical journals in the field of pediatric oncology: Creation of the genuine index scoring system

<div><p>Introduction</p><p>The predominance of English in scientific research has created hurdles for “non-native speakers” of English. Here we present a novel application of native language identification (NLI) for the assessment of medical-scientific writing. For this purpose, we created a novel classification system whereby scoring would be based solely on text features found to be distinctive among native English speakers (NS) within a given context. We dubbed this the “Genuine Index” (GI).</p><p>Methodology</p><p>This methodology was validated using a small set of journals in the field of pediatric oncology. Our dataset consisted of 5,907 abstracts, representing work from 77 countries. A support vector machine (SVM) was used to generate our model and for scoring.</p><p>Results</p><p>Accuracy, precision, and recall of the classification model were 93.3%, 93.7%, and 99.4%, respectively. Class specific F-scores were 96.5% for NS and 39.8% for our benchmark class, Japan. Overall kappa was calculated to be 37.2%. We found significant differences between countries with respect to the GI score. Significant correlation was found between GI scores and two validated objective measures of writing proficiency and readability. Two sets of key terms and phrases differentiating NS and non-native writing were identified.</p><p>Conclusions</p><p>Our GI model was able to detect, with a high degree of reliability, subtle differences between the terms and phrasing used by native and non-native speakers in peer reviewed journals, in the field of pediatric oncology. In addition, L1 language transfer was found to be very likely to survive revision, especially in non-Western countries such as Japan. These findings show that even when the language used is technically correct, there may still be some phrasing or usage that impact quality.</p></div

Genuine index model performance.

<p>Genuine index model performance.</p

Number of abstracts per country.

<p>Number of abstracts per country.</p

Analysis of correlation between national IELTS results and GI scores (n = 15).

<p>Pearson correlation demonstrates statistically significant, albeit minor, correlation between between aggregate GI scores and IELTS scores for the countries where data exists. (A), academic writing: correlation = 0.5485, p = 0.034. (B) general writing: correlation = 0.6009, p = 0.018).</p